Protamine enhances the proliferative activity of hepatocyte growth factor in rats.
The effect of protamine on the proliferative activity of hepatocyte growth factor (HGF) was examined in alpha-naphthyl isothiocyanate-intoxicated rats. Protamine pre-injection increased the hepatocyte labeling index induced by HGF four- to fivefold. A similar effect was also observed in partially hepatectomized rats. Because a cell surface heparin-like substance can bind to HGF and protamine has an affinity for heparin, protamine may affect HGF pharmacokinetics. In fact, protamine injection caused a transient increase in plasma HGF concentrations after administration of HGF and, in vitro, protamine eluted HGF prebound to heparin-Sepharose. Protamine also reduced the plasma clearance of HGF and increased 2.5-fold the exposure of hepatocytes to HGF in vivo. The enhancing effect of protamine on the mitogenic response of hepatocytes to HGF was also observed in vitro (approximately 2-fold after protamine pretreatment compared with HGF alone), suggesting that the enhancing effect of protamine on HGF-induced liver regeneration results from dual effects exerted by protamine 1) lowering the overall elimination of HGF and 2) directly stimulating hepatocyte mitosis induced by HGF.
Liu
K X
KX
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Kato
Y
Y
Kaku
T I
TI
Matsumoto
K
K
Nakamura
T
T
Sugiyama
Y
Y
D015058:1-Naphthylisothiocyanate / Q000633:toxicity; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D017228:Hepatocyte Growth Factor / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008657:Metabolic Clearance Rate; D008940:Mitotic Index / Q000187:drug effects; D011479:Protamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D011479:Protamines; D015058:1-Naphthylisothiocyanate; D017228:Hepatocyte Growth Factor; D004247:DNA